The present invention relates to the field of nucleosides.
Mammalian immune systems contain two major classes of lymphocytes: B lymphocytes (B cells), which originate in the bone marrow; and T lymphocytes (T cells) that originate in the thymus. B cells are largely responsible for humoral immunity (i.e., antibody production), while T cells are largely responsible for cell-mediated immunity.
T cells are generally considered to fall into two subclasses, helper T cells and cytotoxic T cells. Helper T cells activate other lymphocytes, including B cells and cytotoxic T cells, and macrophages, by releasing soluble protein mediators called cytokines that are involved in cell-mediated immunity. As used herein, lymphokines are a subset of cytokines.
Helper T cells are also generally considered to fall into two subclasses, Th1 and Th2.Th1 cells (also known as Type 1 cells) produce interleukin 2 (ILxe2x88x922), tumor necrosis factor (TNFxcex1) and interferon gamma (IFNxcex3), and are responsible primarily for cell-mediated immunity such as delayed type hypersensitivity and antiviral immunity. In contrast, Th2 cells (also known as Type 2 cells) produce interleukins, IL4,ILxe2x88x925,ILxe2x88x926, IL-9,ILxe2x88x9210 and ILxe2x88x921 3,and are primarily involved in assisting humoral immune responses such as those seen in response to allergens, e.g. IgE and IgG4 antibody isotype switching (Mosmann, 1989,Annu Rev Immunol, 7:145-173).
As used herein, the terms Th1 and Th2 xe2x80x9cresponsesxe2x80x9d,are meant to include the entire range of effects resulting from induction of Th1 and Th2 lymphocytes, respectively. Among other things, such responses include variation in production of the corresponding cytokines through transcription, translation, secretion and possibly other mechanisms, increased proliferation of the corresponding lymphocytes, and other effects associated with increased production of cytokines, including motility effects.
The priority applications, each of which is incorporated herein by reference, relate to aspects of our recent discoveries involving the effect of various nucleosides (which are defined herein to include derivatives and analogs of native nucleosides) on selectively modulating lymphocyte responses relative to each other. Among other things, we have shown that either of Th1 and Th2 responses can be selectively suppressed while the other is either induced or left relatively unaffected, and either of Th 1 or Th2 responses can be selectively induced while the other is either suppressed or left relatively unaffected. We have also discovered the surprising fact that nucleosides effective in selectively modulating Th1 and Th2 responses relative to one another tend to have a bimodal effect. Among other things, nucleosides that tend to generally suppress or induce both Th1 and Th1 activity at a relatively higher dose. tend to selectively modulate Th1 and Th2 relative to each other at relatively lower doses.
The mechanisms by which nucleosides and other compounds selectively modulate Th1 and Th2 responses relative to each other are still unclear. One possibility contemplated by the present inventors is that effective nucleosides alter the pool of guanosine triphosphate (GTP), which in turn affects the rate at which cytokines are produced. In this theory, relatively large variations in available GTP are sufficient to affect concentrations of both Th1 and Th2 cytokines, while relatively smaller variations in available GTP tend to affect concentrations of Th1 and Th2 cytokines to different extents.
The effects of 2-xcex2-D-ribofuranosylthiazole-4-carboxamide (Tiazofurin), a synthetic C-nucleoside analogue, on GTP levels supports this view. Tumor cells are characterized by high levels of inosine monophosphate dehydrogenase (IMP DH) activity, and it is known that IMP DH is the rate-limiting enzyme of GTP biosynthesis. Weber, G., IMP Dehydrogenase and GTP as Targets in Human Leukemia Treatment. Adv. Exp. Med. Biol. 309B:287-292 (1991). Tiazofurin has been shown to selectively block IMP DH activity and deplete guanine nucleotide pools, which in turn forces various tumors into remission. Weber, G., Critical Issues in Chemotherapy with Tiazofurin, Adv. Enzyme Regul. 29:75-95 (1989). Typical initial doses of Tiazofurin are about 4,400 mg/m2, with consolidation doses of about 1100 to 3300 mg/m2. At these levels synthesis of both Th1 and Th2 responses are greatly reduced, thereby essentially shutting down much of the immune system. In one aspect of the present invention it is contemplated that much smaller doses of Tiazofurin, in the range of 1/10th to one-half that set forth above, would be sufficient to specifically suppress either a Th1 response or a Th2 response without greatly reducing the other response.
The effects of 1xcex2-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (Ribavirin) also supports the present theory. Ribavirin is a potent, broad-spectrum antiviral agent, which has also been shown to inhibit IMP DH. Yamada, Y. et al., Action of the Active Metabolites of Tiazofurin and Ribavirin on Purified IMP Dehydrogenase, Biochem. 27:2193-2196 (1988). Ribavirin proceeds under a different mechanism than Tiazofurin in inhibiting IMP DH, however, acting on a different site on the enzyme molecule. Ribavirin is converted to its active metabolite, ribavirin-monophosphate (RMP), which inhibits the enzyme at the IMP-XMP site of IMP DH. As with Tiazofurin, the affinity of Ribavirin""s active form to the enzyme is higher than that of the natural metabolite. At relatively high doses, approximately 2200 mg/m2 or about 1200-1500 mg/day for an adult, Ribavirin reduces IMP DH activity to such an extent that both Th1 and Th2 responses are inhibited. At relatively lower dosages of approximately 600 to 1000 mg/day, Ribavirin promotes a Th1 response and suppresses a Th2 response.
Despite the existence of as-yet undefined mechanisms, we have discovered that enormous potential benefits can be derived from selective modulation of Th1 and Th2 responses relative to each other. We have concluded, for example, that specific modulation of Th1 relative to Th2 can be useful in treating a wide variety of conditions and diseases, ranging from infections, infestations, tumors and hypersensitivities to autoimmune diseases.
These discoveries are especially significant because modern treatment strategies for many of the above-listed diseases have limited effectiveness, significant side effects, or both. Treatment of autoimmune disease, for example, is frequently limited to palliative measures, removal of toxic antibodies (as in myasthenia gravis), and administration of hazardous drugs including corticosteroids, chloroquine derivatives, and antimetabolic or antitumor drugs, and drugs such as cyclosporines that target immune system cells.
This application relates to the use of monocyclic nucleosides in a relatively low dosage range to selectively modulate Th1 and Th2 responses relative to each other in the treatment of disease. In one aspect of the invention, administration of a nucleoside or other compound reduces the dosage at which a primary drug is administered. In another aspect of the invention, an abnormality reflected in increased response in one group of cytokines is treated by administering a nucleoside or other compound that increases response in another group of cytokines. In yet another aspect of the invention, a patient is prophylactically treated by administering a nucleoside or other compound that selectively reduces Th1 activity without significantly reducing Th2 activity. In yet another aspect of the invention, a nucleoside or other compound is administered to a patient at a dose that reduces the patient""s GTP pool to a degree that selectively reduces one of the Th1 or Th2 responses without significantly reducing the other response. Controlled release dosage forms are particularly contemplated to achieve that result.
Examples of nucleosides contemplated to be effective in this manner are D- and L-forms of monocyclic nucleosides corresponding to Formula 1.
Examples of primary drugs contemplated to be effective in this manner are anti-viral agents such as Ribavirin, acyclovir, and AZT(trademark); anti-fungal agents such as tolnaftate, Fungizone(trademark), Lotrimin(trademark), Mycelex(trademark), Nystatin and Amphoteracin; anti-parasitics such as Mintezol(trademark), Niclocide(trademark), Vermox(trademark), and Flagyl(trademark); bowel agents such as Immodium(trademark), Lomotil(trademark) and Phazyme(trademark); anti-tumor agents such as Adriamycin(trademark), Cytoxan(trademark), Imuran(trademark), Methotrxate, Mithracin(trademark), Tiazofurin(trademark), Taxol(trademark); dermatologic agents such as Aclovate(trademark), Cyclocort(trademark), Denorex, Florone(trademark), Oxsoralen(trademark), coal tar and salicylic acid; migraine preparations such as ergotamine compounds; steroids and immunosuppresants not listed above, including cyclosporins, Diprosone(trademark), hydrocortisone; Floron(trademark), Lidex(trademark), Topicort and Valisone; and metabolic agents such as insulin.